{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:30:23Z","timestamp":1794047423808,"version":"4.8.0"},"reference-count":70,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"5","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-\/-) male mice aged 4 and 12 months. Eleven-month-old wild-type and Nrf2-\/- mice were fed with either standard diet or a diet containing 2.5% carbonyl-iron (iron overload [IO]) for 4 weeks. We show that Nrf2-\/- mice develop an age-dependent cardiomyopathy, characterized by severe oxidation, degradation of SERCA2A and iron accumulation. This was associated with local hepcidin expression and increased serum non-transferrin-bound iron, which promotes maladaptive cardiac remodeling and interstitial fibrosis related to overactivation of the TGF-b pathway. When mice were exposed to IO diet, the absence of Nrf2 was paradoxically protective against further heart iron accumulation. Indeed, the combination of prolonged oxidation and the burst induced by IO diet resulted in activation of the unfolded protein response (UPR) system, which in turn promotes hepcidin expression independently from heart iron accumulation. In the heart of Hbbth3\/+ mice, a model of b-thalassemia intermedia, despite the activation of Nrf2 pathway, we found severe protein oxidation, activation of UPR system and cardiac fibrosis independently from heart iron content. We describe the dual role of Nrf2 when aging is combined with IO and its novel interrelation with UPR system to ensure cell survival. We open a new perspective for early and intense treatment of cardiomyopathy in patients with b-thalassemia before the appearance of heart iron accumulation.<\/jats:p>","DOI":"10.3324\/haematol.2022.281995","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T03:59:45Z","timestamp":1674705585000},"page":"1335-1348","source":"Crossref","is-referenced-by-count":14,"title":["Duality of Nrf2 in iron-overload cardiomyopathy"],"prefix":"10.3324","volume":"108","author":[{"given":"Enrica","family":"Federti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vinchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iana","family":"Iatcenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ghigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Matte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge Cedrick Mbiandjeu","family":"Toya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Siciliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Chiabrando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Tolosano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven Zebulon","family":"Vance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Riccardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immacolata","family":"Andolfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Iezzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Lamolinara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achille","family":"Iolascon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"De Franceschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"47476","doi-asserted-by":"crossref","unstructured":"Wermke M, Eckoldt J, Gotze KS. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial. Lancet Haematol. 2018; 5(5):e201-e210.","DOI":"10.1016\/S2352-3026(18)30036-X"},{"key":"47477","doi-asserted-by":"crossref","unstructured":"Kumfu S, Fucharoen S, Chattipakorn SC, Chattipakorn N. Cardiac complications in beta-thalassemia: from mice to men. Exp Biol Med (Maywood). 2017; 242(11):1126-1135.","DOI":"10.1177\/1535370217708977"},{"key":"47478","doi-asserted-by":"crossref","unstructured":"Temraz S, Santini V, Musallam K, Taher A. Iron overload and chelation therapy in myelodysplastic syndromes. Crit Rev Oncol Hematol. 2014; 91(1):64-73.","DOI":"10.1016\/j.critrevonc.2014.01.006"},{"key":"47479","doi-asserted-by":"crossref","unstructured":"Kremastinos DT, Farmakis D. Iron overload cardiomyopathy in clinical practice. Circulation. 2011; 124(20):2253-2263.","DOI":"10.1161\/CIRCULATIONAHA.111.050773"},{"key":"47480","doi-asserted-by":"crossref","unstructured":"Dharmarajan K, Rich MW. Epidemiology, pathophysiology, and prognosis of heart failure in older adults. Heart Fail Clin. 2017; 13(3):417-426.","DOI":"10.1016\/j.hfc.2017.02.001"},{"key":"47481","doi-asserted-by":"crossref","unstructured":"Hershko C. Pathogenesis and management of iron toxicity in thalassemia. Ann N Y Acad Sci. 2010; 1202:1-9.","DOI":"10.1111\/j.1749-6632.2010.05544.x"},{"key":"47482","doi-asserted-by":"crossref","unstructured":"Piga A, Longo F, Duca L. High nontransferrin bound iron levels and heart disease in thalassemia major. Am J Hematol. 2009; 84(1):29-33.","DOI":"10.1002\/ajh.21317"},{"key":"47483","doi-asserted-by":"crossref","unstructured":"Ganz T. Systemic iron homeostasis. Physiol Rev. 2013; 93(4):1721-1741.","DOI":"10.1152\/physrev.00008.2013"},{"key":"47484","doi-asserted-by":"crossref","unstructured":"Nemeth E, Tuttle MS, Powelson J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704):2090-2093.","DOI":"10.1126\/science.1104742"},{"key":"47485","doi-asserted-by":"crossref","unstructured":"van Breda GF, Bongartz LG, Zhuang W. Cardiac hepcidin expression associates with injury independent of iron. Am J Nephrol. 2016; 44(5):368-378.","DOI":"10.1159\/000449419"},{"key":"47486","doi-asserted-by":"crossref","unstructured":"Merle U, Fein E, Gehrke SG, Stremmel W, Kulaksiz H. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology. 2007; 148(6):2663-2668.","DOI":"10.1210\/en.2006-1331"},{"key":"47487","doi-asserted-by":"crossref","unstructured":"Mleczko-Sanecka K, Silvestri L. Cell-type-specific insights into iron regulatory processes. Am J Hematol. 2021; 96(1):110-127.","DOI":"10.1002\/ajh.26001"},{"key":"47488","doi-asserted-by":"crossref","unstructured":"Chen QM, Maltagliati AJ. Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics. 2018; 50(2):77-97.","DOI":"10.1152\/physiolgenomics.00041.2017"},{"key":"47489","doi-asserted-by":"crossref","unstructured":"Liu Z, Han K, Huo X. Nrf2 knockout dysregulates iron metabolism and increases the hemolysis through ROS in aging mice. Life Sci. 2020; 255:117838.","DOI":"10.1016\/j.lfs.2020.117838"},{"key":"47490","doi-asserted-by":"crossref","unstructured":"De Franceschi L, Bertoldi M, Matte A. Oxidative stress and beta-thalassemic erythroid cells behind the molecular defect. Oxid Med Cell Longev. 2013; 2013:985210.","DOI":"10.1155\/2013\/985210"},{"key":"47491","doi-asserted-by":"crossref","unstructured":"Li J, Zhang C, Xing Y. Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. Cardiovasc Res. 2011; 90(2):315-324.","DOI":"10.1093\/cvr\/cvr010"},{"key":"47492","doi-asserted-by":"crossref","unstructured":"Wang H, Lai Y, Mathis BJ. Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2. J Mol Cell Cardiol. 2015; 84:143-153.","DOI":"10.1016\/j.yjmcc.2015.04.012"},{"key":"47493","doi-asserted-by":"crossref","unstructured":"Li J, Ichikawa T, Janicki JS, Cui T. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets. 2009; 13(7):785-794.","DOI":"10.1517\/14728220903025762"},{"key":"47494","doi-asserted-by":"crossref","unstructured":"Xing Y, Niu T, Wang W. Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2. PLoS One. 2012; 7(9):e44899.","DOI":"10.1371\/journal.pone.0044899"},{"key":"47495","doi-asserted-by":"crossref","unstructured":"Lim PJ, Duarte TL, Arezes J. Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat Metab. 2019; 1(5):519-531.","DOI":"10.1038\/s42255-019-0063-6"},{"key":"47496","doi-asserted-by":"crossref","unstructured":"Matte A, De Falco L, Iolascon A. The interplay between peroxiredoxin-2 and nuclear factor-erythroid 2 is important in limiting oxidative mediated dysfunction in beta-thalassemic erythropoiesis. Antioxid Redox Signal. 2015; 23(16):1284-1297.","DOI":"10.1089\/ars.2014.6237"},{"key":"47497","doi-asserted-by":"crossref","unstructured":"Kerins MJ, Ooi A. The roles of NRF2 in modulating cellular iron homeostasis. Antioxid Redox Signal. 2018; 29(17):1756-1773.","DOI":"10.1089\/ars.2017.7176"},{"key":"47498","doi-asserted-by":"crossref","unstructured":"Fang X, Wang H, Han D. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A. 2019; 116(7):2672-2680.","DOI":"10.1073\/pnas.1821022116"},{"key":"47499","doi-asserted-by":"crossref","unstructured":"Matte A, De Falco L, Federti E. Peroxiredoxin-2: a novel regulator of iron homeostasis in ineffective erythropoiesis. Antioxid Redox Signal. 2018; 28(1):1-14.","DOI":"10.1089\/ars.2017.7051"},{"key":"47500","doi-asserted-by":"crossref","unstructured":"Schnelle M, Catibog N, Zhang M. Echocardiographic evaluation of diastolic function in mouse models of heart disease. J Mol Cell Cardiol. 2018; 114:20-28.","DOI":"10.1016\/j.yjmcc.2017.10.006"},{"key":"47501","doi-asserted-by":"crossref","unstructured":"Vinchi F, Porto G, Simmelbauer A. Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction. Eur Heart J. 2020; 41(28):2681-2695.","DOI":"10.1093\/eurheartj\/ehz112"},{"key":"47502","doi-asserted-by":"crossref","unstructured":"Andolfo I, Rosato BE, Manna F. Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP\/SMADs pathway. Am J Hematol. 2020; 95(2):188-197.","DOI":"10.1002\/ajh.25683"},{"key":"47503","doi-asserted-by":"crossref","unstructured":"Matte A, Recchiuti A, Federti E. Resolution of sickle cell disease-associated inflammation and tissue damage with 17R-resolvin D1. Blood. 2019; 133(3):252-265.","DOI":"10.1182\/blood-2018-07-865378"},{"key":"47504","doi-asserted-by":"crossref","unstructured":"Federti E, Matte A, Ghigo A. Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension. Free Radic Biol Med. 2017; 112:376-386.","DOI":"10.1016\/j.freeradbiomed.2017.08.004"},{"key":"47505","doi-asserted-by":"crossref","unstructured":"Vinchi F, De Franceschi L, Ghigo A. Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases. Circulation. 2013; 127(12):1317-1329.","DOI":"10.1161\/CIRCULATIONAHA.112.130179"},{"key":"47506","doi-asserted-by":"crossref","unstructured":"Roczkowsky A, Chan BYH, Lee TYT. Myocardial MMP-2 contributes to SERCA2a proteolysis during cardiac ischaemiareperfusion injury. Cardiovasc Res. 2020; 116(5):1021-1031.","DOI":"10.1093\/cvr\/cvz207"},{"key":"47507","doi-asserted-by":"crossref","unstructured":"Schmidt PJ, Racie T, Westerman M. Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of beta-thalassemia intermedia. Am J Hematol. 2015; 90(4):310-313.","DOI":"10.1002\/ajh.23934"},{"key":"47508","doi-asserted-by":"crossref","unstructured":"Erkens R, Kramer CM, Luckstadt W. Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med. 2015; 89:906-917.","DOI":"10.1016\/j.freeradbiomed.2015.10.409"},{"key":"47509","doi-asserted-by":"crossref","unstructured":"Zhang C, Wang Y, Ge Z. GDF11 Attenuated ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC through down-regulating CCL11 in mice. Curr Mol Med. 2018; 18(10):661-671.","DOI":"10.2174\/1566524019666190204112753"},{"key":"47510","doi-asserted-by":"crossref","unstructured":"Cao X, Mao M, Diao J. Ectopic Overexpression of PPARgamma2 in the heart determines differences in hypertrophic cardiomyopathy after treatment with different thiazolidinediones in a mouse model of diabetes. Front Pharmacol. 2021; 12:683156.","DOI":"10.3389\/fphar.2021.683156"},{"key":"47511","doi-asserted-by":"crossref","unstructured":"Temsah RM, Netticadan T, Chapman D. Alterations in sarcoplasmic reticulum function and gene expression in ischemic-reperfused rat heart. Am J Physiol. 1999; 277(2):H584-594.","DOI":"10.1152\/ajpheart.1999.277.2.H584"},{"key":"47512","doi-asserted-by":"crossref","unstructured":"French JP, Quindry JC, Falk DJ. Ischemia-reperfusion-induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition. Am J Physiol Heart Circ Physiol. 2006; 290(1):H128-136.","DOI":"10.1152\/ajpheart.00739.2005"},{"key":"47513","doi-asserted-by":"crossref","unstructured":"Das SK, Wang W, Zhabyeyev P. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Sci Rep. 2015; 5:18132.","DOI":"10.1038\/srep18132"},{"key":"47514","doi-asserted-by":"crossref","unstructured":"Silveira C, Campos DHS, Freire PP. Importance of SERCA2a on early isolated diastolic dysfunction induced by supravalvular aortic stenosis in rats. Braz J Med Biol Res. 2017; 50(5)","DOI":"10.1590\/1414-431x20175742"},{"key":"47515","doi-asserted-by":"crossref","unstructured":"Tsika RW, Ma L, Kehat I. TEAD-1 overexpression in the mouse heart promotes an age-dependent heart dysfunction. J Biol Chem. 2010; 285(18):13721-13735.","DOI":"10.1074\/jbc.M109.063057"},{"key":"47516","doi-asserted-by":"crossref","unstructured":"Neef S, Maier LS. Novel aspects of excitation-contraction coupling in heart failure. Basic Res Cardiol. 2013; 108(4):360.","DOI":"10.1007\/s00395-013-0360-2"},{"key":"47517","doi-asserted-by":"crossref","unstructured":"Prathipati P, Metreveli N, Nandi SS, Tyagi SC, Mishra PK. Ablation of matrix metalloproteinase-9 prevents cardiomyocytes contractile dysfunction in diabetics. Front Physiol. 2016; 7:93.","DOI":"10.3389\/fphys.2016.00093"},{"key":"47518","doi-asserted-by":"crossref","unstructured":"Yadav SK, Kambis TN, Kar S, Park SY, Mishra PK. MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro. Cell Death Dis. 2020; 11(3):186.","DOI":"10.1038\/s41419-020-2367-6"},{"key":"47519","doi-asserted-by":"crossref","unstructured":"Iwabuchi M, Sheng H, Thompson JW. Characterization of the ubiquitin-modified proteome regulated by transient forebrain ischemia. J Cereb Blood Flow Metab. 2014; 34(3):425-432.","DOI":"10.1038\/jcbfm.2013.210"},{"key":"47520","doi-asserted-by":"crossref","unstructured":"Sato Y, Kobayashi H, Sato S. Systemic accumulation of undigested lysosomal metabolites in an autopsy case of mucolipidosis type II; autophagic dysfunction in cardiomyocyte. Mol Genet Metab. 2014; 112(3):224-228.","DOI":"10.1016\/j.ymgme.2014.05.001"},{"key":"47521","doi-asserted-by":"crossref","unstructured":"Peikert K, Federti E, Matte A. Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis. Acta Neuropathol Commun. 2021; 9(1):81.","DOI":"10.1186\/s40478-021-01181-y"},{"key":"47522","doi-asserted-by":"crossref","unstructured":"Zhai X, Wang W, Sun S. 4-Hydroxy-2-nonenal promotes cardiomyocyte necroptosis via stabilizing receptor-interacting serine\/threonine-protein kinase 1. Front Cell Dev Biol. 2021; 9:721795.","DOI":"10.3389\/fcell.2021.721795"},{"key":"47523","doi-asserted-by":"crossref","unstructured":"Lu J, Sun B, Huo R. Bone morphogenetic protein-2 antagonizes bone morphogenetic protein-4 induced cardiomyocyte hypertrophy and apoptosis. J Cell Physiol. 2014; 229(10):1503-1510.","DOI":"10.1002\/jcp.24592"},{"key":"47524","doi-asserted-by":"crossref","unstructured":"Aschemeyer S, Qiao B, Stefanova D. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood. 2018; 131(8):899-910.","DOI":"10.1182\/blood-2017-05-786590"},{"key":"47525","doi-asserted-by":"crossref","unstructured":"Li J, Ichikawa T, Villacorta L. Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol. 2009; 29(11):1843-1850.","DOI":"10.1161\/ATVBAHA.109.189480"},{"key":"47526","doi-asserted-by":"crossref","unstructured":"Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res. 2004; 94(12):1543-1553.","DOI":"10.1161\/01.RES.0000130526.20854.fa"},{"key":"47527","doi-asserted-by":"crossref","unstructured":"Ge C, Hu L, Lou D. Nrf2 deficiency aggravates PM2.5-induced cardiomyopathy by enhancing oxidative stress, fibrosis and inflammation via RIPK3-regulated mitochondrial disorder. Aging (Albany NY). 2020; 12(6):4836-4865.","DOI":"10.18632\/aging.102906"},{"key":"47528","doi-asserted-by":"crossref","unstructured":"Szostek-Mioduchowska AZ, Lukasik K, Skarzynski DJ, Okuda K. Effect of transforming growth factor -beta1 on alpha-smooth muscle actin and collagen expression in equine endometrial fibroblasts. Theriogenology. 2019; 124:9-17.","DOI":"10.1016\/j.theriogenology.2018.10.005"},{"key":"47529","doi-asserted-by":"crossref","unstructured":"Gallini R, Lindblom P, Bondjers C, Betsholtz C, Andrae J. PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Exp Cell Res. 2016; 349(2):282-290.","DOI":"10.1016\/j.yexcr.2016.10.022"},{"key":"47530","doi-asserted-by":"crossref","unstructured":"Kalra K, Eberhard J, Farbehi N, Chong JJ, Xaymardan M. Role of PDGF-A\/B ligands in cardiac repair after myocardial infarction. Front Cell Dev Biol. 2021; 9:669188.","DOI":"10.3389\/fcell.2021.669188"},{"key":"47531","doi-asserted-by":"crossref","unstructured":"Vecchi C, Montosi G, Zhang K. ER stress controls iron metabolism through induction of hepcidin. Science. 2009; 325(5942):877-880.","DOI":"10.1126\/science.1176639"},{"key":"47532","doi-asserted-by":"crossref","unstructured":"Lee JM. Nuclear receptors resolve endoplasmic reticulum stress to improve hepatic insulin resistance. Diabetes Metab J. 2017; 41(1):10-19.","DOI":"10.4093\/dmj.2017.41.1.10"},{"key":"47533","doi-asserted-by":"crossref","unstructured":"Minakshi R, Rahman S, Jan AT, Archana A, Kim J. Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer. Exp Mol Med. 2017; 49(11)","DOI":"10.1038\/emm.2017.215"},{"key":"47534","doi-asserted-by":"crossref","unstructured":"Dickhout JG, Carlisle RE, Austin RC. Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ Res. 2011; 108(5):629-642.","DOI":"10.1161\/CIRCRESAHA.110.226803"},{"key":"47535","doi-asserted-by":"crossref","unstructured":"Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta. 2013; 1832(7):940-947.","DOI":"10.1016\/j.bbadis.2012.11.011"},{"key":"47536","doi-asserted-by":"crossref","unstructured":"Chinprateep B, Ratanasit N, Kaolawanich Y. Prevalence of left ventricular diastolic dysfunction by cardiac magnetic resonance imaging in thalassemia major patients with normal left ventricular systolic function. BMC Cardiovasc Disord. 2019; 19(1):245.","DOI":"10.1186\/s12872-019-1235-8"},{"key":"47537","doi-asserted-by":"crossref","unstructured":"Spirito P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation. 1990; 82(1):88-94.","DOI":"10.1161\/01.CIR.82.1.88"},{"key":"47538","doi-asserted-by":"crossref","unstructured":"Korf-Klingebiel M, Kempf T, Schluter KD. Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. Circulation. 2011; 123(5):504-514.","DOI":"10.1161\/CIRCULATIONAHA.110.989665"},{"key":"47539","doi-asserted-by":"crossref","unstructured":"Murphy CJ, Oudit GY. Iron-overload cardiomyopathy: pathophysiology, diagnosis, and treatment. J Card Fail. 2010; 16(11):888-900.","DOI":"10.1016\/j.cardfail.2010.05.009"},{"key":"47540","doi-asserted-by":"crossref","unstructured":"Gu J, Cheng Y, Wu H. Metallothionein is downstream of Nrf2 and partially mediates sulforaphane prevention of diabetic cardiomyopathy. Diabetes. 2017; 66(2):529-542.","DOI":"10.2337\/db15-1274"},{"key":"47541","doi-asserted-by":"crossref","unstructured":"Tian C, Gao L, Zucker IH. Regulation of Nrf2 signaling pathway in heart failure: Role of extracellular vesicles and non-coding RNAs. Free Radic Biol Med. 2021; 167:218-231.","DOI":"10.1016\/j.freeradbiomed.2021.03.013"},{"key":"47542","doi-asserted-by":"crossref","unstructured":"Maejima Y. The critical roles of protein quality control systems in the pathogenesis of heart failure. J Cardiol. 2020; 75(3):219-227.","DOI":"10.1016\/j.jjcc.2019.09.019"},{"key":"47543","doi-asserted-by":"crossref","unstructured":"Gotoh T, Oyadomari S, Mori K, Mori M. Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem. 2002; 277(14):12343-12350.","DOI":"10.1074\/jbc.M107988200"},{"key":"47544","doi-asserted-by":"crossref","unstructured":"Lenna S, Trojanowska M. The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis. Curr Opin Rheumatol. 2012; 24(6):663-668.","DOI":"10.1097\/BOR.0b013e3283588dbb"},{"key":"47545","doi-asserted-by":"crossref","unstructured":"Nakada EM, Sun R, Fujii U, Martin JG. The impact of endoplasmic reticulum-associated protein modifications, folding and degradation on lung structure and function. Front Physiol. 2021; 12:665622.","DOI":"10.3389\/fphys.2021.665622"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2022.281995\/75307","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2022.281995\/75570","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/10954\/75307","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:03:19Z","timestamp":1794045799000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/haematol.2022.281995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,26]]},"references-count":70,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2022.281995","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2023,1,26]]}}}